Involvement of N-methyl-D-aspartate (NMDA) receptors in respiratory rhythmogenesis

Abstract

The involvement of N-methyl-D-aspartate (NMDA) subtype of glutamate receptors in the control of inspiratory termination was studied in paralyzed decerebrated cats. Cats were either vagotomized, or had intact vagus nerves and were ventilated with a ventilator driven by the discharge of the phrenic nerve. The systemic administration of NMDA antagonists acting non-competitively (MK-801, ketamine, phencyclidine) or competitively (2-amino-7-phosphonoheptanoic acid: AP7), produced an apneusis in vagotomized animals or in animals transiently deprived of vagal pulmonary feedback by the 'no inflation test'. After NMDA receptor blockade, the inspiratory phase could be terminated by lung inflation or sensory stimulation. Thus pharmacologically distinct mechanisms control the termination of inspiration: vagal afferents which are NMDA-independent, and a central mechanism acting through the activation of NMDA receptors. The apneustic pattern induced by NMDA receptor blockade was characterized by a decrease of the amplitude of integrated phrenic nerve activity, the persistence of CO2 sensitivity and an enhancement of apneusis by anaesthesia. After injection of NMDA antagonists there was a decrease of the duration of expiration which thereafter remained constant and dissociated from inspiratory duration. The possible mechanisms by which NMDA receptors may contribute to respiratory rhythmogenesis are discussed.